Emami, S.; Westerlund, E.; Rojas Converso, T.; Johansson-Lindbom, B.; Persson, J. J.

Group A Streptococcus (GAS; Streptococcus pyogenes) is an important bacterial pathogen estimated to cause over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae in the world yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >200 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyze the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells, is accompanied by an altered cytokine profile upon subsequent infection and requires macrophages and the macrophage-activating cytokine IFN-{gamma}. To our knowledge these findings are the first to suggest that GAS has the ability to induce forms of trained innate immunity. Taken together, the current study reveals a novel mechanism of the innate immune system in responses to GAS infections that potentially could be leveraged for future development of effective vaccines.